Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). This study was financed in part by the Coordenacão de Aperfeicoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001....

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Authors: Fintelman-Rodrigues, Natalia, Sacramento, Carolina Q., Lima, Carlyle Ribeiro, Silva, Franklin Souza da, Ferreira, André C., Mattos, Mayara, Freitas, Caroline S. de, Soares, Vinicius Cardoso, Dias, Suelen da Silva Gomes, Temerozo, Jairo Ramos, Miranda, Milene Dias, Matos, Aline R., Bozza, Fernando A., Carels, Nicolas, Alves, Carlos Roberto, Siqueira, Marilda Agudo Mendonça Teixeira de, Bozza, Patrícia T., Souza, Thiago Moreno L.
Format: article
Status:Published version
Publication Date:2020
Country:Brasil
Institution:Fundação Oswaldo Cruz (FIOCRUZ)
Repository:Repositório Institucional da FIOCRUZ (ARCA)
Language:English
OAI Identifier:oai:arca.fiocruz.br:icict/40679
Online Access:https://arca.fiocruz.br/handle/icict/40679
Access Level:Open access
Keyword:COVID-19
SARS-CoV-2
ATV
Atazanavir
Molecular Dynamic Analysis
RTV
Ritonavir
Chloroquine
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dc.title.none.fl_str_mv Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
title Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
spellingShingle Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
Fintelman-Rodrigues, Natalia
COVID-19
SARS-CoV-2
ATV
Atazanavir
Molecular Dynamic Analysis
RTV
Ritonavir
Chloroquine
title_short Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
title_full Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
title_fullStr Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
title_full_unstemmed Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
title_sort Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
dc.creator.none.fl_str_mv Fintelman-Rodrigues, Natalia
Sacramento, Carolina Q.
Lima, Carlyle Ribeiro
Silva, Franklin Souza da
Ferreira, André C.
Mattos, Mayara
Freitas, Caroline S. de
Soares, Vinicius Cardoso
Dias, Suelen da Silva Gomes
Temerozo, Jairo Ramos
Miranda, Milene Dias
Matos, Aline R.
Bozza, Fernando A.
Carels, Nicolas
Alves, Carlos Roberto
Siqueira, Marilda Agudo Mendonça Teixeira de
Bozza, Patrícia T.
Souza, Thiago Moreno L.
author Fintelman-Rodrigues, Natalia
author_facet Fintelman-Rodrigues, Natalia
Sacramento, Carolina Q.
Lima, Carlyle Ribeiro
Silva, Franklin Souza da
Ferreira, André C.
Mattos, Mayara
Freitas, Caroline S. de
Soares, Vinicius Cardoso
Dias, Suelen da Silva Gomes
Temerozo, Jairo Ramos
Miranda, Milene Dias
Matos, Aline R.
Bozza, Fernando A.
Carels, Nicolas
Alves, Carlos Roberto
Siqueira, Marilda Agudo Mendonça Teixeira de
Bozza, Patrícia T.
Souza, Thiago Moreno L.
author_role author
author2 Sacramento, Carolina Q.
Lima, Carlyle Ribeiro
Silva, Franklin Souza da
Ferreira, André C.
Mattos, Mayara
Freitas, Caroline S. de
Soares, Vinicius Cardoso
Dias, Suelen da Silva Gomes
Temerozo, Jairo Ramos
Miranda, Milene Dias
Matos, Aline R.
Bozza, Fernando A.
Carels, Nicolas
Alves, Carlos Roberto
Siqueira, Marilda Agudo Mendonça Teixeira de
Bozza, Patrícia T.
Souza, Thiago Moreno L.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.en.none.fl_str_mv COVID-19
SARS-CoV-2
ATV
Atazanavir
Molecular Dynamic Analysis
RTV
Ritonavir
Chloroquine
topic COVID-19
SARS-CoV-2
ATV
Atazanavir
Molecular Dynamic Analysis
RTV
Ritonavir
Chloroquine
description This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). This study was financed in part by the Coordenacão de Aperfeicoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. Funding was also provided by CNPq, CAPES and FAPERJ through the National Institutes of Science and Technology Program (INCT) to Carlos Morel (INCT-IDPN). Thanks are due to Oswaldo Cruz Foundation/FIOCRUZ under the auspicious of Inova program.
publishDate 2020
dc.date.accessioned.fl_str_mv 2020-04-08T02:59:47Z
dc.date.available.fl_str_mv 2020-04-08T02:59:47Z
dc.date.issued.fl_str_mv 2020
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv FINTELMAN-RODRIGUES, Natalia et al. Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production. bioRxiv, p. 1-28, 2020.
dc.identifier.uri.fl_str_mv https://arca.fiocruz.br/handle/icict/40679
dc.identifier.doi.none.fl_str_mv 10.1101/2020.04.04.020925
identifier_str_mv FINTELMAN-RODRIGUES, Natalia et al. Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production. bioRxiv, p. 1-28, 2020.
10.1101/2020.04.04.020925
url https://arca.fiocruz.br/handle/icict/40679
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instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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spelling 2020-04-08T02:59:47Z2020-04-08T02:59:47Z2020FINTELMAN-RODRIGUES, Natalia et al. Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production. bioRxiv, p. 1-28, 2020.https://arca.fiocruz.br/handle/icict/4067910.1101/2020.04.04.020925This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). This study was financed in part by the Coordenacão de Aperfeicoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. Funding was also provided by CNPq, CAPES and FAPERJ through the National Institutes of Science and Technology Program (INCT) to Carlos Morel (INCT-IDPN). Thanks are due to Oswaldo Cruz Foundation/FIOCRUZ under the auspicious of Inova program.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil / Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Universidade Iguaçu. Nova Iguaçu, RJ, Brasil / Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisas em Timo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico Em Saúde. Rio de Janeiro, RJ, Brasil / National Institute of Science and Technology for Innovation on Diseases of Neglected Populations (INCT-IDPN). Rio de Janeiro, RJ, Brasil.Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratório e do Sarampo. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Instituto D’or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brasil.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the ongoing pandemic of 2019 CoV disease (COVID-19), which is already responsible for far more deaths than were reported during the previous public health emergencies of international concern provoked by two related pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of any clinically approved drug that could be repurposed to combat COVID-19 would allow the rapid implementation of potentially life-saving procedures to complement social distancing and isolation protocols. The major protease (Mpro) of SARS-CoV-2 is considered a promising target for drug interventions, based on results from related CoVs with lopinavir (LPV) an HIV protease inhibitor, that that can inhibit the Mpro of 2002 SARS-CoV. However, limited evidence exists for other clinically approved anti-retroviral protease inhibitors that may bind more efficiently to Mpro from SARS-CoV-2 and block its replication. Of high interest is atazanavir (ATV) due to its documented bioavailability within the respiratory tract, which motivated our evaluation on its ability to impair SARS-CoV-2 replication through a series of in vitro experiments. A molecular dynamic analysis showed that ATV could dock in the active site of SARS-CoV-2 Mpro with greater strength than LPV and occupied the substrate cleft on the active side of the protease throughout the entire molecular dynamic analysis. In a cell-free protease assay, ATV was determined to block Mpro activity at a concentration of 10 μM. Next, a series of assays with in vitro models of virus infection/replications were performed using three cell types, Vero cells, a human pulmonary epithelial cell line and primary human monocytes, which confirmed that ATV could inhibit SARS-CoV-2 replication, alone or in combination with ritonavir (RTV). In addition, the virus-induced levels of IL-6 and TNF-α were reduced in the presence of these drugs, which performed better than chloroquine, a compound recognized for its anti-viral and anti-inflammatory activities. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.engAtazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine productioninfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleCOVID-19SARS-CoV-2ATVAtazanavirMolecular Dynamic AnalysisRTVRitonavirChloroquineNão Publicadoinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZFintelman-Rodrigues, NataliaSacramento, Carolina Q.Lima, Carlyle RibeiroSilva, Franklin Souza daFerreira, André C.Mattos, MayaraFreitas, Caroline S. deSoares, Vinicius CardosoDias, Suelen da Silva GomesTemerozo, Jairo RamosMiranda, Milene DiasMatos, Aline R.Bozza, Fernando A.Carels, NicolasAlves, Carlos RobertoSiqueira, Marilda Agudo Mendonça Teixeira deBozza, Patrícia T.Souza, Thiago Moreno L.LICENSElicense.txtlicense.txttext/plain; charset=utf-83132https://arca.fiocruz.br/bitstreams/46538842-408a-45c0-8d8b-eb4b17c34808/download70425d8cb6e40fdcf4edd2ef0660b45bMD51falseAnonymousREADORIGINAL2020.04.04.020925v2.full.pdf2020.04.04.020925v2.full.pdfVersão 2application/pdf3011733https://arca.fiocruz.br/bitstreams/47e314f7-0e41-4ed1-87b4-a41002102be9/downloadb3cb9bd190799b1d1470da6deca84714MD53trueAnonymousREAD2020.04.04.020925v1.full.pdf2020.04.04.020925v1.full.pdfVersão 1application/pdf1430850https://arca.fiocruz.br/bitstreams/9d8f16de-e303-44df-b596-a6e9c466acb6/downloadd4676ac2d4a5797f9f1d2e527a20ed02MD52falseAnonymousREADmedia-1.pdfmedia-1.pdfMaterial Suplementarapplication/pdf604492https://arca.fiocruz.br/bitstreams/2e1f8a2b-cd60-4bf7-b888-2ba1cf7da6e0/download97400d921879f1565cab55e27d92b4b0MD54falseAnonymousREADTEXT2020.04.04.020925v2.full.pdf.txt2020.04.04.020925v2.full.pdf.txtExtracted texttext/plain56907https://arca.fiocruz.br/bitstreams/f9159deb-2616-4c3a-8059-be2c4ce143cc/download1f1b2fce01605103040bf6d4dc46501dMD529falseAnonymousREAD2020.04.04.020925v1.full.pdf.txt2020.04.04.020925v1.full.pdf.txtExtracted texttext/plain59473https://arca.fiocruz.br/bitstreams/a43927e0-9e19-4969-a766-8a2dd0bac65d/download397364f026efffcedb3f48c08e22518eMD531falseAnonymousREADmedia-1.pdf.txtmedia-1.pdf.txtExtracted texttext/plain4603https://arca.fiocruz.br/bitstreams/62d9c76f-4d37-4e0e-b2ea-206bd3c005da/download4ec2721e2f01e7d705fc77813a145ec5MD533falseAnonymousREADTHUMBNAIL2020.04.04.020925v2.full.pdf.jpg2020.04.04.020925v2.full.pdf.jpgGenerated Thumbnailimage/jpeg30016https://arca.fiocruz.br/bitstreams/547fb74a-c825-40d0-b0b8-66be620f4f29/download8571b81c6bdad72cf233d9babfe66af6MD530falseAnonymousREAD2020.04.04.020925v1.full.pdf.jpg2020.04.04.020925v1.full.pdf.jpgGenerated Thumbnailimage/jpeg30033https://arca.fiocruz.br/bitstreams/c74a5df3-9cb5-4d81-a5bb-e96b579a9239/download17d6ad5f66d5045217cf12548d39ffeeMD532falseAnonymousREADmedia-1.pdf.jpgmedia-1.pdf.jpgGenerated Thumbnailimage/jpeg31755https://arca.fiocruz.br/bitstreams/3ddadbfe-befc-4d77-837c-96d18a6daae3/download338c682678c77e7a02dfa04948a0c65cMD534falseAnonymousREADicict/406792025-12-11 08:34:13.699open.accessoai:arca.fiocruz.br:icict/40679https://arca.fiocruz.brRepositório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352025-12-11T11:34:13Repositório Institucional da FIOCRUZ (ARCA) - 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score 15,300724

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